| Summary: | A heterozygous mutation in the TRK-Fused Gene (TFG1) has recently been identified in hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P). TFG1 protein is reportedly localized at endoplasmic reticulum (ER) exit sites and modulates ER export, but the mechanism of its action in neurodegeneration remains unclear. To clarify the molecular pathogenesis of HMSN-P, we examined the biochemical and cellular characteristics of wild-type and mutant (P285L) TFG1 in vitro. A coexpression study of human TFG1 and ER substrates, which are degraded by the ubiquitin–proteasome system (UPS), showed that TFG1 is an inhibitory regulator of the UPS. Deletion mutant constructs revealed that the proline/glutamine-rich domain in TFG1 was critical for regulation of the UPS and proper localization at ER exit sites. Furthermore, overexpression of wild-type TFG1 increased ubiquitination of ER-resident proteins and led to ER stress. Mutant (P285L) TFG1, which is in the proline/glutamine-rich domain, enhanced the inhibitory effect on the UPS and the level of ER stress. These data provide new pathological insights into HMSN-P, and we suspect that the pathogenesis is tightly associated with disruption of intracellular protein homeostasis and ER stress.
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